Posted by: Thixia | August 9, 2008

Aquaporins

 

Aquaporins are a class of integral membrane proteins or more commonly referred to as a class of major intrinsic proteins (MIP) that forms in the membrane of biological cells.

Genetic defects involving aquaporin genes have been associated with several human diseases. The 2003 Nobel Prize in Chemistry was awarded to Peter Agre for the discovery of aquaporins and jointly to Roderick MacKinnon for his work on the structure and operation of ion channels.
 
 

 

Sideview of Aquaporin 1 (AQP1) Channel

 Function

 

Aquaporins selectively conduct water molecules in and out, while preventing the passage of ions

and other solutes. Also known as water channels, aquaporins are membrane pore proteins. Aquaporins are commonly composed of four (typically) identical subunit proteins in mammals, with each monomer acting as a water channel.
Water molecules traverse through the pore of the channel in single file. The presence of water channels increases membrane permeability to water.

Many human cell types express them, as do certain bacteria and many other organisms, such as plants for which it is essential for the water transport system.

 

 

 

 

 

 Structure of Aquaporin

History

 

In most cells, water moves in and out by diffusion through the lipid component of cell membranes. Due to the relatively high water permeability of some epithelial cells it was long suspected that some additional mechanism for water transport across membranes must exist, but it was not until the discovery of the first aquaporin, ‘aquaporin-1’.

 

AQP1

 

 

 

 

 

Structure

 

Aquaporins are made up of six transmembrane α-helices arranged in a right-handed bundle, with the amino and the carboxyl termini located on the cytoplasmic surface of the membrane. The amino and carboxyl halves of the sequence show similarity to each other, in what appears to be a tandem repeat. Some researches believe that this results from an early evolution event which saw the duplication of the half sized gene. There are also five interhelical loop regions (A – E) that form the extracellular and cytoplasmic vestibules. Loops B and E are hydrophobic loops which contain the highly, although not completely conserved Asn-Pro-Ala (NPA) motif, which overlap the middle of the lipid bilayer of the membrane forming a 3-D ‘hourglass’ structure where the water flows through. This overlap forms one of the two well-known channel constriction sites in the peptide, the NPA motif and a second and usually narrower constriction known as ‘selectivity filter’ or ar/R selectivity filter.
Aquaporins form tetramers in the cell membrane, and facilitate the transport of water and, in some cases, other small uncharged solutes, such as glycerol, CO2, ammonia and urea across the membrane depending on the size of the pore. The different aquaporins contain differences in their peptide sequence which allows for the size of the pore in the protein to differ between aquaporins. The resultant size of the pore directly affects what molecules are able to pass through the pore, with small pore sizes only allowing small molecules like water to pass through the pore. However, the water pores are completely impermeable to charged species, such as protons, a property critical for the conservation of membrane’s electrochemical potential.
 
 

 

 

Using computer simulations, it has been suggested that the orientation of the water molecules moving through the channel assures that only water passes between cells, due to the formation of a single line of water molecules. The water molecules move through the narrow channel by orienting themselves in the local electrical field formed by the atoms of the channel wall. Upon entering, the water molecules face with their oxygen atom down the channel. Midstream, they reverse orientation, facing with the oxygen atom up. This rotation of the water molecules in the pore is caused by the interaction of hydrogen bonds between the oxygen of the water molecule and the asparagines in the two NPA motifs. While passing through the channel, the single-file chain of water molecules streams through, always entering face down and leaving face up. The strictly opposite orientations of the water molecules keep them from conducting protons via the Grotthuss mechanism, while still permitting a fast flux of water molecules.

 

Aquaporins and disease

 

There have been two clear examples of diseases identified as resulting from mutations in aquaporins:

Mutations in the aquaporin-2 gene cause hereditary nephrogenic diabetes insipidus in humans.

Mice homozygous for inactivating mutations in the aquaporin-0 gene develop congenital cataracts.

A small number of people have been identified with severe or total deficiency in aquaporin-1. Interestingly, they are generally healthy, but exhibit a defect in the ability to concentrate solutes in the urine and to conserve water when deprived of drinking water. Mice with targeted deletions in aquaporin-1 also exhibit a deficiency in water conservation due to an inability to concentrate solutes in the kidney medulla by counter-current multiplication.

In addition to its role in genetically determined nephrogenic diabetes insipidus, aquaporins also play a key role in acquired forms of nephrogenic diabetes insipidus (disorders that cause increased urine production). Acquired nephrogenic diabetes insipidus can result from impaired regulation of aquaporin-2 due to administration of lithium salts (as a treatment for bipolar disorder), low potassium concentrations in the blood (hypokalemia), high calcium concentrations in the blood (hypercalcemia), or a chronically high intake of water beyond the normal requirements (e.g. due to excessive habitual intake of bottled water or coffee).
Aquaporin 4 is found in the basolateral cell membrane of principal collecting duct cells and provide a pathway for water to exit these cells.

 

 
 

 

 

Finally, it has been found that autoimmune reactions against aquaporin 4 produce Devic’s disease.

  
AQP channel

 

 

 

 

 

 

 

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